Abstract
BackgroundIt was reported recently that resveratrol could sensitize a number of cancer cells to the antitumoral effects of some conventional chemotherapy drugs. The current study was designed to investigate whether resveratrol could sensitize leukemic cells to proteasome inhibitors.MethodsLeukemic cells were treated with MG132 alone or in combination with resveratrol. Cell viability was investigated using MTT assay, and induction of apoptosis and cell cycle distribution was measured using flow cytometry. Western blot and real-time RT-PCR were used to investigate the expression of FOXO1 and p27Kip1. CHIP was performed to investigate the binding of FOXO1 to the p27 Kip1 promoter.ResultsResveratrol strongly reduced cytotoxic activities of proteasome inhibitors against leukemic cells. MG132 in combination with resveratrol caused cell cycle blockade at G1/S transition via p27Kip1 accumulation. Knockdown of p27Kip1 using siRNA dramatically attenuated the protective effects of resveratrol on cytotoxic actions of proteasome inhibitors against leukemic cells. Resveratrol induced FOXO1 expression at the transcriptional level, while MG132 increased nuclear distribution of FOXO1. MG132 in combination with resveratrol caused synergistic induction of p27Kip1 through increased recruitment of FOXO1 on the p27Kip1 promoter.ConclusionsResveratrol may have the potential to negate the cytotoxic effects of proteasome inhibitors via regulation of FOXO1 transcriptional activity and accumulation of p27Kip1.
Highlights
It was reported recently that resveratrol could sensitize a number of cancer cells to the antitumoral effects of some conventional chemotherapy drugs
Resveratrol suppresses the cytotoxic effects of proteasome inhibitors in K562 leukemic cells Cell viability of K562 cells was decreased upon treatment with resveratrol when used higher concentration than 50 μM, while 1-20 μM of resveratrol had no obvious effects on K562 cell viability within 24 h (Figure 1A)
MG132-induced apoptosis was further determined by flow-cytometric analysis of K562 cells labeled with propidium iodide (PI) and annexin V
Summary
It was reported recently that resveratrol could sensitize a number of cancer cells to the antitumoral effects of some conventional chemotherapy drugs. A number of previous studies have reported that resveratrol can inhibit the growth of human cancer cells when it is present alone at rather high concentrations (usually >50 uM) [5,6,7,8]. It has been reported when it is used in combination with other anticancer drugs, resveratrol can avoid some of the debilitating side effects and sensitize a number of cancer cell lines to the anticancer actions of some other conventional chemotherapy drugs such as TNFa, paclitaxel, et al, as well as radiotherapy [5,6,7,9,10,11,12,13]. It has been reported that p27Kip1-mediated cell cycle arrest at G1/S transition is required for protection against proteasome inhibitors [18]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
